BackgroundReasons for Th2 skewing in IgE‐mediated food allergies remains unclear. Clinical observations suggest impaired T cell activation may drive Th2 responses evidenced by increased atopic manifestations in liver transplant patients on tacrolimus (a calcineurin inhibitor). We aimed to assess differentiation potential, T cell activation and calcium influx of naïve CD4+ T cells in children with IgE‐mediated food allergies.MethodsPeripheral blood mononuclear cells from infants in the Starting Time for Egg Protein (STEP) Trial were analyzed by flow cytometry to assess Th1/Th2/Treg development. Naïve CD4+ T cells from children with and without food allergies were stimulated for 7 days to assess Th1/Th2/Treg transcriptional factors and cytokines. Store operated calcium entry (SOCE) was measured in children with and without food allergies. The effect of tacrolimus on CD4+ T cell differentiation was assessed by treating stimulated naïve CD4+ T cells from healthy volunteers with tacrolimus for 7 days.ResultsEgg allergic infants had impaired development of IFNγ+ Th1 cells and FoxP3+ transitional CD4+ T cells compared with non‐allergic infants. This parallels reduced T‐bet, IFNγ and FoxP3 expression in naïve CD4+ T cells from food allergic children after in vitro culture. SOCE of naïve CD4+ T cells was impaired in food allergic children. Naïve CD4+ T cells treated with tacrolimus had reduced IFNγ, T‐bet, and FoxP3, but preserved IL‐4 expression.ConclusionsIn children with IgE‐mediated food allergies, dysregulation of T helper cell development is associated with impaired SOCE, which underlies an intrinsic impairment in Th1 and Treg differentiation. Along with tacrolimus‐induced Th2 skewing, this highlights an important role of SOCE/calcineurin pathway in T helper cell differentiation.

中文翻译：

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钙内流受损是 IgE 介导的食物过敏儿童 T 辅助细胞分化失衡的基础


背景 IgE 介导的食物过敏中 Th2 偏向的原因仍不清楚。临床观察表明，T 细胞活化受损可能会驱动 Th2 反应，这一点可以通过服用他克莫司（一种钙调神经磷酸酶抑制剂）的肝移植患者特应性表现增加来证明。我们的目的是评估 IgE 介导的食物过敏儿童中幼稚 CD4+ T 细胞的分化潜力、T 细胞活化和钙流入。方法通过流式细胞术分析鸡蛋蛋白起始时间 (STEP) 试验中婴儿的外周血单核细胞，评估 Th1/Th2/Treg 发育。来自有或没有食物过敏的儿童的初始 CD4+ T 细胞被刺激 7 天，以评估 Th1/Th2/Treg 转录因子和细胞因子。对有或没有食物过敏的儿童进行了商店操作的钙输入（SOCE）测量。通过用他克莫司处理健康志愿者刺激的幼稚 CD4+ T 细胞 7 天来评估他克莫司对 CD4+ T 细胞分化的影响。结果与非过敏婴儿相比，鸡蛋过敏婴儿的 IFNγ+ Th1 细胞和 FoxP3+ 过渡 CD4+ T 细胞的发育受损。这与食物过敏儿童的幼稚 CD4+ T 细胞在体外培养后的 T-bet、IFNγ 和 FoxP3 表达减少相似。食物过敏儿童中幼稚 CD4+ T 细胞的 SOCE 受损。用他克莫司处理的幼稚 CD4+ T 细胞减少了 IFNγ、T-bet 和 FoxP3，但保留了 IL-4 表达。 结论在 IgE 介导的食物过敏儿童中，T 辅助细胞发育失调与 SOCE 受损有关，SOCE 是一种内在的机制。 Th1 和 Treg 分化受损。 连同他克莫司诱导的 Th2 偏差，这凸显了 SOCE/钙调磷酸酶途径在 T 辅助细胞分化中的重要作用。